This research proposal is aimed at understanding the mechanisms through which the nuclear receptor, PPARgamma, acts to ameliorate Alzheimer's Disease (AD)related pathology in animal models and improves cognition in AD patients. PPARgamma is a ligand activated transcription factor whose activity is known to regulate glucose, lipid and energy metabolism. Importantly, it has also been shown to exhibit potent anti-inflammatory actions. Recent studies from this laboratory have shown that PPARgamma activation results in a reduction of plaque deposition, soluble Apound42 levels and inflammatory markers in V7171hAPP mice. Furthermore, PPARgamma activation results in the stimulation of Apound clearance from the medium. However, the underlying mechanism through which Abeta clearance is achieved is unknown. In the brain, A/?peptides are synthesized at high rates and are cleared at equally efficient rates. Any disruption in the production or clearance of Abeta can lead to its accumulation and depostion within the brain. Thus, we hypothesize that understanding mechanisms associated with Ay? clearance are of significance in slowing disease progression. In this proposal, we seek to elucidate mechanisms through which PPARgamma activation results in the degradation of soluble A/?species. We provide preliminary data that PPARgamma activation leads to the degradation of Apound and induces the expression of genes including ApoE and those that are responsible for its lipidation. We anticipate PPARgamma activation increases ApoE lipidation status by inducing the expression of LXR and its target genes ABCA1. Lipidated ApoE then acts to chaperone the proteolytic degradation of Abeta. This application is of particular interest because PPARgamma agonists are now being clinically evaluated for treatment of AD. Thus, it is of importance to understand the mechanisms through which PPARgamma exerts salutary effects on the degradation of soluble AB that may underly its therapeutic utility for disease treatment. [unreadable] [unreadable] [unreadable]